A Perspective on the Ethics of Clinical Medical Research on Human Subjects
Richard Garlikov
The following is the essential initial line of reasoning involving the general ethics of clinical medical research involving experimental interventions on human subjects. While some of this paper may have application to more general research involving human beings, its focus is what is normally called “therapeutic research”, and by that we mean simply research involving interventions that testexperimental therapies, particularly in regard to phase II and phase III types of studies that seek to find out whether an intervention is safe and effective.It is not about phase I research, nor about non-therapeutic research, such as participation in a retrospective study or a survey.
Proposition 1)Medical progress requires medical research.
Proposition 2)Medical progress benefits future patients with the condition for which progress occurs.
Proposition 3)Medical research sometimes requires experimentation with newly tried treatments (i.e., experimental treatments) for human subjects.
Proposition 4)Experimental treatments can be dangerous and result in serious harm or death.
Proposition 5)Benefitting patients is the justification for conducting research that is risky or potentially dangerous.
Proposition 6)Therefore (from 1, 3, and 4) medical research and medical progress can sometimes be risky and result in serious harm or death.
Proposition 7)Because of the risks involved, medical experimentation with human subjects requires the most rigorous scientific validity in order to be ethical, because to put people at risk for no good reason (i.e., to put people at risk in order to obtain results that are not necessarily accurate or meaningful) would be morally wrong.
Proposition 8)There are other conditions besides scientific invalidity that make putting innocent people at risk morally unjustifiable also, such as doing so without their consent, doing so in ways that the likelihood or quality of the potential benefit is not commensurate with the risk or magnitude of the potential harm for the subject.
Proposition 9)Therefore (from 6, 7, and 8), the most rigorous scientific validity is a necessary, but not sufficient, condition in order for experimentation with human subjects to be ethical.
Proposition 10)The most rigorous scientific validity requires using random, double-blind, placebo-control trials in medical research.
Proposition 11)Scientifically rigorous and valid random control trials require strict adherence to treatments that cannot be individualized.
Proposition 12)Some subjects in random control trials receive placebo treatment or experimental treatment that is not tailored to their individual needs.
Proposition 13)Hence, (from 12) some subjects in random control trials do not receive the best treatment for their conditions.
Proposition 14)It is unethical for a physician not to use the best treatment available for a patient and it is unethical for a physician to recommend to a patient that the patient participate in a program of treatment, such as a research program, in which the patient will not receive, and/or will not be able to receive, the best treatment available, and which may also be dangerous, harmful, or fatal for the patient.
Proposition 15)Hence (from 13 and 14), it is unethical for physicians to utilize patients as research subjects or to recommend they participate in medical research.
Moreover,
Proposition 16)It would be morally wrong to harm or put people at risk against their will or in a manner that would be against their will.[1],[2]
Proposition 17)Thus, utilizingpeople as research subjects in ways against their will or in a manner that would be against their will,would be morally wrong.
Proposition 18)People who give valid consent to participation in a research project are not being utilized against their will or in a manner that would be against their will.
Proposition 19)Hence (from 17 and 18), valid consent to participate in a research program is a sufficient condition for not utilizing (or exploiting) people in medical experiments against their will or in a manner that would be against their will. And not utilizing people against their will or in a manner that would be against their will is a necessary but not sufficient condition for conducting research on human subjects in a morally right way.
(Note: this does not logically imply that valid consent is sufficient for conducting research on those who give it. And this also does not logically imply that valid consent is necessary for treating subjects experimentally either[3]. For something to be a sufficient condition to meet a necessary condition is just to say it is one way to meet a requirement that itself is not sufficient. E.g., to obtain a college undergraduate degree, it is often sufficient to take an art history course to meet a humanities requirement, and it is often necessary to meet a humanities requirement to obtain an undergraduate degree, but that does not make taking an art history course either necessary or sufficient to obtain a college undergraduate degree.)
Proposition 20)If patients, no matter what they are told, still mistakenly believe that they will definitely receive treatment instead of a placebo, and if they mistakenly believe there is minimal or no risk to being a research subject, or that the potential benefits are commensurate with the risk, then their informed consent is not valid consent or is not rational consent.
Proposition 21)According to studies, many research subjects mistakenly believe that they will definitely receive treatment instead of a placebo and they mistakenly believe there is no or minimal risk to receiving the experimental treatment, or they believe the potential benefits are commensurate with the risk.
Proposition 22)Hence, many patients should not be research subjects (i.e., research on experimental treatments should not be conducted on these patients/subjects).
There is evidence against the premises preceded by arrows: propositions 7, 9, 10, 11, 14, and 15. We will argue that those statements, as they stand, are indeed false, and that some of the arguments to overcome the objections to them will not suffice. In some cases, however, those statements can be replaced by true statements which do not cause as many problems.
We will also argue that some of the arguments meant to refute the above arguments or false propositions are unsound or miss the point. In some cases other arguments will serve that purpose better.
Problem of Placebo Controls
And the Problem of Risk of Harm From an Experimental Treatment
It should be fairly clear from the above that placebo controls and the potential dangers of experimental treatments cause two different kinds of problems, and are in some ways the lynchpin of two significant ethical concerns in conducting research on human subjects – 1) causing actual harm to (or at least not helping benefit) research subjects or 2) exploiting people by conducting research on them that subjects them to the risk of harm (or lack of benefit in the case of placebo), even when harm does not actually occur.
Consider first the alleged problem of using placebo-controls:
“Randomized double-blind placebo-controlled trials have been argued to provide the strongest test of efficacy and, as such, are important tools for advancing the evidence base supporting [...] treatment. However, such trials present difficult ethical issues, because one group, by definition, receives no treatment for the condition being studied.”[i]
This may be put in the form of the dilemma that if one uses placebos in research, one will not be “treating” (i.e., administering to)patients (i.e., benefitting them through actual treatment) as one should be administering to them; and if one does not use placebos in research, one will not be doing proper research. Thus, one must choose between taking care of patients properly and doing research properly.[4]
This dilemma is often characterized as the dilemma between a utilitarian consequentialist approach to ethics (the obligation to do what will bring about the greatest balance of good for the greatest number of people) and a “deontological” approach to ethics that says there are some things more important than just bringing about the greatest balance of good for everyone – that, for example, people should be treated with respect and not “used” at their expense to gain benefits for others, particularly they should not be used by those who have taken an oath to place their health and well-being first.[5]
Consider also a parallel dilemma involving the risks and dangers for the subject of experimental research:
If one harms human subjects in research, one will be treating them maleficently and abrogating the obligation to “do no harm”thus not treating people as one should be treating them; and if one does not test treatments – even if the treatments might or do cause harm -- one will not be doing proper research. Thus, one must choose between taking care of patients properly and doing research properly.
Taken together, these two dilemmas are expressed in proposition 14 (and consequently in 15 also) above.
While there are many fine articles that have contributed to the discussion of individual elements of the arguments we are considering – articles which make excellent, insightful, reasonable, and sometimes passionately eloquent points -- this paper is intended to offer a more systematicand, in a sense fundamental, philosophical analysis of theunderlying issues involved, showing their relationship to each other and to the overall topic.
Furthermore, the authors will contend that there can be some valid controlled studies that satisfy the underlying logic of randomized double-blind, placebo-control or “no treatment” control trials [RCT] even without withholding treatment from anyone.
With this as background, we would now like to examine the initial line of reasoning presented at the beginning of this paper and those answers and ensuing arguments generally given in response to it.
The conventionally accepted response to the dilemma is to deny the truth of proposition 14 (and subsequently proposition 15) by invoking the concept of equipoise, which comes in two forms, with the distinction and significance between them to be explained shortly: theoretical equipoise and clinical equipoise. The basic idea of equipoise is that it is not a breach of the duties of beneficence and non-maleficence if, without professional negligence, one truly does not know which act will bring about the greatest benefit or will cause more harm than good for a subject. “Equipoise” is the word that describes a non-negligent, lack of sufficient knowledge/evidence about which treatment option, if any, is best for the patient or subject, and therefore absolves the physician or researcher for conducting research on subjects or patients, and absolves a physician for recommending to patients that they join a research trial or for condoning a patient’s joining such a trial, even if the patient receives no treatment or a placebo (and thus is not given a real treatment) and is not benefitted by medical care as such, and even if the patient is harmed by the treatment.
What the principle of equipoise in research ethics does is to allow research to be conducted on proposed (or existing) therapies when the result is uncertain and may actually benefit the subject who has the condition for which the therapy is intended or used. This is because the researcher (whether physician or not) then does not already know the answer to the question as to which treatment (or whether non-treatment) is best for the patient or for similar patients and therefore is not intentionally (or negligently) harming or intentionally (or negligently) refraining from helping the subject by placing the subject in one arm of the study rather than another. And the physician is not intentionally harming or refraining from helping the subject by encouraging or allowing the subject to participate in the study.
In propositions 14 and, the term “unethical” and its implied antonym, “ethical” are ambiguous -- in some cases referring to what is right or wrong, and in other cases referring to what is morally responsible, conscientious, and reasonable, or what is morally irresponsible and culpable. What turns out to be wrong, for example, given full information (which normally appears only in hindsight or after the fact), is not always morally culpable or unreasonable. Putting or allowing a patient to be in a research project’s control arm, where the experimental arm yields benefits, is wrong (in the sense of outcome) but is not culpable or blameworthy since one could not know the outcome prior to the placement. Similarly, but opposite, when a treatment turns out to be harmful, the right thing to do would have been to put one’s patients in the control group instead of the treatment group, even though the above dilemmas might have made that seem to be a violation of the Hippocratic oath, when, prior to the trial, the experimental arm seemed to be the one most likely beneficial.
While ethical principles seek to accomplish what is actually right, they cannot hold one culpable for non-negligent ignorance that leads to err. While utilitarianism, for example, is the principle of doing the greatest good (i.e., bringing about the greatest benefit) for the greatest number, one is not normally morally culpable for falling short of that if one in fact does the act which all available evidence would lead any rational and knowledgeable person to believe would bring about the greatest good for the greatest number, but which ends up not doing so. Unfortunately, since people are not omniscient, and must instead use logic based on reasonably best available evidence, the intended goal, is not always achieved. The most reasonable act based on all available evidence is not always the act that turns out to be right. This is not just a problem for utilitarianism or other “consequentialist theories” (i.e., theories of right that involve reference to the best actual results or consequences), but it applies to all ethical theories, since what most rationally seems, for example, to be treating a person with respect may not be what actually respects that person. E.g., if you visit someone in the hospital who is seriously or terminally ill, that may not be what they want, even if it might be what most people might want. Or arguing with most people makes them feel you are not respecting them, whereas many people feel that arguing with them shows them you respect their opinions enough to challenge them and that you respect the person enough to want to show him/her what is best for them, even though that takes effort on your part and even though you risk being disliked by them for being thought to be arrogant, controlling, or argumentative.
It might be thought that given we can at best only be accountable for being non-negligently rational, that principles such as utilitarianism or the Hippocratic Oath should be worded as: “one should do what one rationally and non-negligently believes is best for all or for the patient.” Or that “one should do what one rationally and non-negligently believes shows the most respect for other people.” And while it is true in one sense that those are things one “should” do, it is also the case that doing that will not necessarily be the right thing to do – will not turn out to be correct. Ethical principles and obligations need to refer to what is objectively right, not just to what is rational, or otherwise everyone who is rational and who has best intentions would be automatically right even when what they do turns out to actually have terrible consequences or override someone else’s rights by mistake. It is important linguistically and conceptually that we keep the distinction between what is right and what is rational, so that when the two do not coincide, we have a way of pointing that out. Ethical principles need to refer to what is actually right, but moral character involves non-negligently doing what all available evidence would rationally say that is. So there is a distinction between being right and being reasonable. People should always (try to) do what is right, but they can only be held accountable for being (non-negligently) reasonable in the attempt. In this particular context of the above dilemmas, being “non-negligent” includes being current in the professional knowledge one should have.
Applying that idea to the concept of equipoise, as it is used to try to justify research on human beings, when such research may include no (beneficent) treatment (i.e., placebo) or actual harm, the idea is that if a physician or researcher does his/her best in trying to help an ill or injured patient while also seeking scientific knowledge, the physician or researcher, as long as s/he is reasonable and non-negligently knowledgeable is not morally culpable even if the subject turns out in actuality not to be helped, or even to be harmed. Hence, as long as a competent physician is not conducting or recommending a research study that will knowingly likely harm the patient as subject, s/he is not violating his/her oath or any reasonable ethical principle about treating people decently.[6]
However, since Benjamin Freedman’s contribution to this subject (referenced below), “equipoise” relevant to research appears in two forms, 1) “theoretical” or individual equipoise, whereby the individual researcher does not already know what is in the subject’s best interest, and 2) “clinical” or professional equipoise, whereby the profession “as a whole” (however that might reasonablybe understood or determined to mean) does not know, or cannot agree, on what is the best course of action for the subject with the condition. Since Freedman introduced the distinction, clinical equipoise is generally considered the important form necessary to justify research on human subjects, in order to prevent justifying research because of the mere hunches or beliefs of an individual researcher when that seems to ignore the professionally received view based on prior research evidence. It is the profession’s collective uncertainty about what is considered best treatment, not the individual’s uncertainty that is considered to be important.[7].